Current immunosuppression used to treat transplant patients has decreased the incidence of T cell mediated acute rejection episodes and graft loss. In contrast, the incidence of acute antibody-mediated rejection (AMR) is increasingly observed in clinical transplants and treatment to prevent graft loss during AMR has become a significant problem in transplantation. The mechanisms underlying antibody-mediated mechanisms of renal graft injury and loss remain poorly understood. Investigation into these mechanisms is hampered by the lack of animal models to study the development of donor-specific antibody response and subsequent allograft injury. This absence has also hindered the design of strategies to inhibit antibody-mediated graft acute and chronic graft pathology. The long-term goal of this program is to provide a clearer understanding of inflammatory mechanisms underlying renal allograft acute and chronic injury during AMR. This program comprises three established and interactive investigators who will utilize novel mouse models of renal transplantation and AMR. The overall goal of this program is to delineate mechanisms that lead to the production of renal allograft-reactive antibodies and mechanisms of the antibody-mediated acute and chronic injury of graft tissue. The Specific Aims of this program are: 1) to test how helper T cell signals and innate immune signals shape alloantigen- and autoantigen-specific antibody responses in renal allograft recipients; 2) to test the impact of anti-donor clas I and class II MHC antibodies and autoantibodies on acute and chronic renal allograft injury; 3) to test the role of innate immune activation during antibody-mediated acute allograft injury; and, 4) to test the role of innate immune activation during the initiation and progression of antibody- mediated chronic allograft injury. We expect that the results of this integrated program will: 1) provide novel insights into mechanisms underlying the production of antibodies to allogeneic MHC molecules and to autoantigens in renal transplants; 2) provide novel insights into the mechanisms of acute and chronic injury to renal allografts; and, 3) identify novel targets to inhibit the incidence and intensity of AMR that leads to early and late loss of renal grafts.